Can a nomogram predict apical prostate cancer pathology upgrade from fusion biopsy to final pathology? A multicenter study

Abstract Background This study evaluates the efficacy of a nomogram for predicting the pathology upgrade of apical prostate cancer (PCa). Methods A total of 754 eligible patients were diagnosed with apical PCa through combined systematic and magnetic resonance imaging (MRI)‐targeted prostate biopsy followed by radical prostatectomy (RP) were retrospectively identified from two hospitals (training: 754, internal validation: 182, internal–external validation: 148). A nomogram for the identification of apical tumors in high‐risk pathology upgrades through comparing the results of biopsy and RP was established incorporating statistically significant risk factors based on univariable and multivariable logistic regression. The nomogram's performance was assessed via the receiver operating characteristic (ROC) curve, calibration plots, and decision curve analysis (DCA). Results Univariable and multivariable analysis identified age, targeted biopsy, number of targeted cores, TNM stage, and the prostate imaging‐reporting and data system score as significant predictors of apical tumor pathological progression. Our nomogram, based on these variables, demonstrated ROC curves for pathology upgrade with values of 0.883 (95% CI, 0.847–0.929), 0.865 (95% CI, 0.790–0.945), and 0.840 (95% CI, 0.742–0.904) for the training, internal validation and internal–external validation cohorts respectively. Calibration curves showed good consistency between the predicted and actual outcomes. The validation groups also showed great generalizability with the calibration curves. DCA results also demonstrated excellent performance for our nomogram with positive benefit across a threshold probability range of 0–0.9 for the training and internal validation group, and 0–0.6 for the internal–external validation group. Conclusion The nomogram, integrating clinical, radiological, and pathological data, effectively predicts the risk of pathology upgrade in apical PCa tumors. It holds significant potential to guide clinicians in optimizing the surgical management of these patients.


| INTRODUCTION
Prostate cancer (PCa) remains a leading malignancy among men globally, with approximately 1.41 million new cases diagnosed in 2020, making it the second most common and the fifth deadliest cancer among males worldwide. 1Although some tools were made to improve the detection rate of clinically significant prostate cancer (csPCa) and reduce the number of useless biopsies, prostate biopsy is still the golden standard for the diagnosis of PCa. 2,3The management of prostate cancer is primarily guided by the Gleason score (GS) obtained from prostate biopsies.While biopsies driven by prostate-specific antigen (PSA) testing can facilitate early therapeutic intervention for this potentially fatal condition, discrepancies between GS from biopsy samples and final pathology from whole mount sections are prevalent, exhibiting concordance rates between 28% and 68%. 4 It is important to highlight that approximately 50% of patients initially assessed with a GS of 3 + 3 may undergo an upward revision in their disease status after undergoing radical prostatectomy (RP). 5This variability underscores the challenges in accurately staging PCa, potentially leading to suboptimal treatment decisions.Nevertheless, assessing the risk of disease reclassification according to the standard clinical index remains imperfect, resulting in patient anxiety, avoidable treatment, and imprecision in monitoring. 6,7][10] Optimizing apical dissection to balance cancer control and sphincter preservation is a delicate task that directly impacts postoperative continence. 11Previous studies indicated sparing a portion of the apex during RP might potentially improve postoperative continence and potency. 12Efforts have been made to avoid unnecessary radical surgery and preserve as much membranous urethral length as possible, which in turn may affect the degree of resection near the prostate apex, thus leading to a higher risk of a positive surgical margin (PSM) of the apical lesion.Although fluorescent confocal microscopy (FCM) was used to assess the urethral and ureteral margins in real-time and showed adequate diagnostic performance, it has not been widely used in the clinic. 13Therefore, the identification of potential clinically significant prostate cancer (csPCa) at the apex is important in terms of surgical approach selection.The nomogram model, serving as a visual tool for multifactorial calibration, has risen to prominence for its capacity to amalgamate various clinical data.This enables personalized risk assessments and aids in the guidance of therapeutic decisions. 14his study aims to develop a nomogram that incorporates clinical, radiological, and pathological data to identify patients at high risk of apical tumor pathology upgrades, comparing biopsy results with RP findings to refine surgical approaches and improve patient outcomes.

| Study design and participants
This retrospective study was conducted in accordance with Institutional Review Board approved protocols.Personal identifiers were removed and all data were analyzed anonymously.We meticulously selected 606 patients diagnosed with apical low-risk PCa via cognitive magnetic resonance imaging (MRI) targeted biopsy combined with transrectal ultrasound-guided (TRUS) transperineal systematic prostate biopsy and then underwent RP at Peking Union Medical College Hospital (PUMCH) between January 2018 and October 2022.A total of 148 patients were recruited in Tianjin Medical University General Hospital (TMUGH) from September 2018 to September 2021, adhering to the following inclusion criteria.Biopsy indications included: (1) total serum PSA > 10.0 ng/mL; (2) total serum PSA between 4.0 and 10.0 ng/mL with a free to total PSA ratio (f/t PSA) <0.16 or a PSA density (PSAD) >0.15; (3) abnormal digital rectal examination (DRE); and (4) suspicious findings on TRUS or mpMRI.Apical tumors are defined as malignant lesions located exclusively within the apical region of the prostate, without consideration of malignancies in other locations.As a result, patients with PCa confined only to nonapical zones are not included in this study.According to the National Comprehensive Cancer Network (NCCN) Guidelines, a low-risk PCa lesion detected on a prostate biopsy is classified as Grade Group 1. 15 A stringent set of exclusion holds significant potential to guide clinicians in optimizing the surgical management of these patients.

| MpMRI protocol and scoring criteria
In our center, all patients scheduled for a prostate biopsy undergo a prebiopsy multiparametric MRI (mpMRI) examination.This mpMRI is performed within 1 month following the initial diagnosis of elevated PSA levels in our outpatient department.All MRI images were acquired with a 3-mm section thickness.T2-weighted images in the sagittal, coronal, and axial planes, diffusion-weighted images (b value up to 1500 s/mm 2 ) in the axial plane, dynamic contrast-enhanced images were all obtained based on the European Consensus Meeting (ESUR) on standardization of prostate MRI (More details in Table S1) 16 Prostate imaging-reporting and data system (PI-RADS) score of 3 or greater subsequently underwent a prostate biopsy.Two experienced radiologists with at least 5 years of experience and subspecialization in genitourinary interpreted the mpMRI images and marked the regions of interest.Inter-reader agreement for PI-RADS was evaluated with Cohen's kappa.As conventionally classified, κ values of 0-0.20 defined poor agreement; 0.21-0.40,fair agreement; 0.41-0.60,moderate agreement; 0.61-0.80,substantial agreement; and 0.81-1.0,nearly perfect agreement. 17With the patient in the lithotomy position, a standard systematic prostate biopsy was initially conducted, two cores based on the prostate biopsy protocol were performed at the apical site, and then 2-5 targeted samples from each MRI region of interest were obtained. 18The horizontal section of the prostate was divided into 12 (12-core biopsy) areas numbered as shown in Figure S1.Finally, each core specimen was stored, labeled, fixed in 10% formaldehyde solution, and sent for pathological examination.The 2014 ISUP system was applied to assess the GS.Laparoscopy RP was conducted through an extraperitoneal approach and five trocar techniques. 19onsidering the low amount of lymph node metastasis found in the low intermediate-risk group, it is arguable that pelvic lymphadenectomy may be omitted for prognostic reason according to the standard of NCCN.All biopsy and whole-mount surgical pathology results were reviewed and reported by a single fellowship-trained genitourinary surgical pathologist with at least 15 years of experience.The apical tumor in the biopsy specimen was identified as prostate cancer present in core number 11, number 12, or both.The RP specimens were systematically sectioned and entirely embedded into 5 mm thick blocks.We defined an apical tumor as either the complete tumor or a portion thereof that is situated within 1 cm of the distal end of the RP specimen.Oncological outcomes for apical lesions, as determined from both biopsy and RP specimens, were evaluated in accordance with the TNM 2002 classification system.These outcomes were then directly compared to examine their clinical relevance and consistency.

| Outcome measures and data analysis
All 754 patients from the two hospitals were utilized as a single training cohort for the development of the model and subsequent internal validation.Of these, 606 patients from PUMCH were randomly allocated into two groups in a 7:3 ratio, yielding subsets of 424 and 182 patients through the use of random numbers.The latter group, consisting of 182 patients, was chosen for internal validation.Additionally, 148 patients from TMUGH were enlisted as an internal-external validation cohort.The training cohort was applied for the following univariable, multivariable analysis, and model building, while the validation cohort was used to validate the feasibility of the proposed model.Clinical data were collected from hospital electronic medical records, including age, PSA, free to total PSA (f/t PSA), prostate volume (PV), PSAD, DRE findings, PI-RADS score, number of cores taken, number of cores targeted, number of positive cores, TNM stage, biopsy GS, and International Society of Urological Pathology (ISUP) histopathological findings.PV was calculated from mpMRI measurements of the prostate using the ellipsoid formula (height × width × length × π/6).
The normality of data distribution was first assessed using the Shapiro-Wilk test.The mean ± SD was applied to describe data in a normal distribution, while the median and interquartile range (IQR) were applied for data in a skewed distribution.The univariable logistic regression analysis was initially applied to assess different variables and calculate the odds ratio (OR) with a 95% confidence interval (95% CI).Then, potential statistical significance (p < 0.05) variables were selected for a multivariable logistic analysis by performing both-direction stepwise selection to confirm the final variables.A nomogram for the identification of apical tumors in high-risk pathology upgrades through comparing the results of biopsy and RP was established incorporating statistically significant results based on multivariable logistic regression.The area under the curve (AUC) was generated to investigate the discriminative ability of our nomogram.The calibration curves were then generated to compare the nomogrampredicted probabilities with actual observed outcomes, establishing the model's accuracy.Additionally, the decision curve analysis (DCA) quantified the nomogram's clinical utility by measuring net benefits across various threshold probabilities in both training and validation cohorts, with its clinical significance inferred from the model's deviation from the "All" and "None" reference curves. 20The analysis was performed using "R" for Windows version 4.01 by the rms package.
Biochemical recurrence (BCR) analysis was generated from the initial time of RP until BCR or the last available follow-up.Subsequent follow-up was assigned every 3 months for 2 years, then every 6 months for 3 years, and yearly afterward for each patient.BCR post-RP is defined as at least two consecutive PSA values that are 0.2 ng/mL or higher 21 and assessed through the Kaplan-Meier analysis.The relationship between apical tumor pathology upgrade and positive surgical margin was examined using the Chi-square test, with a significance level set at p < 0.05 (two-sided).

| Univariable and multivariable analysis for apical tumor pathology upgrade
The statistically significant different variables between nonupgraded and upgraded groups for the apical zone   3). Figure 3 shows the nomogram constructed for the biopsy GS upgrade based on the coefficient of the aforementioned six significant predictors.The AUCs were 0.883 (95% CI, 0.847-0.929),0.865 (95% CI, 0.790-0.945),and 0.840 (95% CI, 0.742-0.904) in the training, internal validation and internal-external validation datasets, respectively (p = 0.169), which indicated that the model had a good discrimination ability (Figure 4A-C).Moreover, the calibration curve of the nomogram for the probability of apical tumor pathology upgrade demonstrated a good agreement between prediction and observation for both sets, the slope of the calibration curve was close to the 45-degree line (intercept = 0.014, 0.067, and 0.129), respectively, (Figure 5A-C) which means the model's predicted probabilities are largely consistent with the observed outcomes.DCA was used to test the clinical usefulness of the model.DCA curves in the training and validation cohorts also demonstrated robust potential for clinical application and indicated significant net benefits across the range of 0-0.9 for the training and internal validation group, and 0-0.6 for the internal-external validation group.(Figure 6A-C).
In this study, all participating patients were subjected to RP with comprehensive apical dissection.However, our nomogram reveals that such an extensive procedure could have been avoided for 196 of these patients.
According to the nomogram's predictions, the likelihood of an apical tumor pathology upgrade in these cases was below 20%.

| DISCUSSION
In the present study, we established a nomogram capable of accurately predicting the risk of pathology upgrades in PCa.So far as we know, this is the first study investigating the prediction of apical tumor GS upgrade through the comparison of biopsy results and postoperative pathology, accompanied by the follow-up analysis to explore the prognosis and pathological features of apical prostate lesions.In a previous study, the nomogram developed by Alqahtani et al.  combined PSA levels and PI-RADS to predict pathology upgrades.Jordan Nasri et al. 23 investigated pathology upgrade within a cohort of 426 patients who underwent RP between 2014 and 2021 with an AUC of 0.87; nevertheless, their results did not separate apical tumors from non-apical tumors, underscoring the unique contribution of our research.We believe that our nomogram can facilitate the identification of apical tumor pathology upgrades in RP specimens before surgery, thereby enhancing the strategic planning of apical dissections.
Various studies have emphasized the effect of preserving the apical complex for early recovery of continence.In general, apical dissection includes separating the prostate from the rectum posteriorly, separating neurovascular bundles laterally, dividing and ligating the dorsal venous complex, and transecting the urethra at the prostatic urethral junction.In addition, the apex is one of the most common locations of PSM and an essential site of BCR after therapy.Therefore, it is important to balance the contradiction between the large-scale surgical resection of periprostatic tissue and the risk of PSM occurrence and dysfunction. 24,25Generally, the classification of apical PSM as either benign or malignant is in dispute.Marcq et al. 26 proved that the presence of focal apical positive margins did not increase the risk of BCR.Different explanations were formulated to explain why positive margins were more common at the apex, but the conclusion remains to be controversial.Reasons contributing to this considerable site-specific PSM rate include the absence of a true anatomic prostatic capsular at the anterior side of the apex, the extreme proximity of the urethral continence mechanism requiring an adjacent surgical margin, and the dilemma in obtaining surgical exposure within a constricted space. 27In the present study, we observed higher PSM and BCR rates in the apical tumor pathology upgrade group than the nonupgrade group.With adequate clinical information, patients harboring clinically insignificant apical tumors at low risk of pathology upgrade could benefit from preserving the maximum length of the urethra and surrounding periurethral tissues during apical dissection, thereby offering enhanced protection of urinary continence.Conversely, patients at a high risk Currently, the utilization of image-fusion technology to minimize sampling errors through targeted biopsy represents a significant advancement.In a study, Goel et al. 28 demonstrated that targeted biopsies are associated with significantly less pathology upgrade at surgery when compared with systematic biopsies alone.
In the present study, we proved that whether a targeted biopsy was performed is a clinically significant factor in predicting apical tumor pathology.Therefore, an additional target biopsy is strongly recommended for patients with suspected apical tumor lesions based on MRI results.According to the study of Hossack et al., 29 different prostate biopsy approaches may have an impact on the tumor detection rate of different prostate regions and transperineal prostate biopsy performs better to detect tumors in the apical zone.In addition, transperineal prostate biopsy using a prostate mapping technique has demonstrated a higher detection rate for malignancies, coupled with a reduced incidence of postoperative infections and sepsis. 30A systematic review evaluating pain in 3 studies comparing transperineal versus transrectal biopsies revealed that the transperineal approach significantly increased patient pain (RR: 1.83 [1.27-2.65]). 31It is widely recognized that the prostate apex is a particularly sensitive area during TRUSguided prostate biopsies due to the dominant somatic nerve supply to the region below the dentate line.The necessity for sedation or general anesthesia arises from patient comfort considerations, given the extensive positioning required for placing a stepper and grid, in addition to the discomfort associated with each skin puncture for biopsy samples.Especially, obtaining anterior tissue of the prostate apex by TRUS-guided prostate biopsy is a painful procedure.Kim et al. 33 proved that the total of 14-core prostate biopsies performed (with an extra 2 cores taken from the anterior apex) were likely to cause more severe pain at the apex compared to the conventional 10-to 12-core biopsy procedures.Thus, we recommend conducting a transperineal biopsy under general anesthesia in patients with suspected apical lesions.Up to now, the optimal number of cores to be obtained during a systematic prostate biopsy, particularly in cases of negative multiparametric mpMRI and/ or when complemented by a targeted fusion biopsy for the diagnosis of csPCa remains undetermined. 346][37] These findings led the European Association of Urology guidelines to recommend that three to five biopsy cores be obtained for each target, while the American Association of Urology and the Society of Abdominal Radiology recommended that only two biopsy cores be obtained for each target in the consensus statement. 38The primary objective of targeted biopsy is to minimize the risk of overlooking PCa or undersampling lesions.Our study has proved that increasing the number of biopsies taken from apical suspicious regions of the prostate could significantly increase the accuracy of targeted biopsy.Moreover, it introduces an optimized strategy for targeting and sampling apical tumors in men, utilizing clinically significant primary mpMRI findings in conjunction with our nomogram.
Inevitably, some certain limitations in our study should be highlighted.Firstly, the study is retrospective and the bias in the process of the patient selection cannot be neglected.Nevertheless, we strictly generated the inclusion and exclusion criteria, which made the data we collected more homogeneous and truly reflective of the actual situation.Secondly, we did not perform subgroup analysis based on the low risk of PCa and the very low risk of PCa patients; this indicates the need for collecting more patient data for relevant clinical insights to refine our study in the future.Finally, our definition of an apical prostate tumor has not been validated and might be considered arbitrary; nevertheless, this definition has been applied in similar prior studies. 39e to the small number of enrolled patients, we did not remove patients with high-risk lesions in other locations when calculating BCR, resulting in biased results.In the future, our team will continue our research to provide new methods for nomograms for the diagnosis of PCa pathology upgrade.Despite these limitations, our nomogram has demonstrated its efficacy and utility as a model, effectively aiding clinicians in delivering personalized treatment strategies.

| CONCLUSION
Our study introduces a comprehensive nomogram integrating clinical, radiological, and pathological data, proven to effectively predict pathology upgrades in PCa.In the apical zone, increasing the quantity of biopsy from the region of interest of the apex could significantly decrease the rate of pathology upgrade.We believe our research could provide guidance in personalizing treatment selection for patients with apical tumors, particularly those at low risk of pathology upgrade, by informing more nuanced surgical approach decisions.

12 FENG
et al. criteria was developed to determine the eligibility of patients for participation at both research institutions.These criteria include: (1) Patients without PCa according to biopsy results.(2) Enrollment was limited to patients with complete baseline clinicopathological information and follow-up data.Any case lacking in this respect was excluded from consideration.(3) Patients who underwent neoadjuvant androgen deprivation therapy before undergoing RP were excluded.Written informed consent was obtained from all enrolled patients.The patient selection flow chart is demonstrated in Figure 1.The study was carried out in accordance with the Declaration of Helsinki and was approved by the Research Ethics Committee of Peking Union Medical College (I-22PJ417).

F I G U R E 3
Nomogram predicting apical tumor pathology upgrade.F I G U R E 4 (A) Receiver operating characteristic (ROC) curve of the nomogram for predicting apical tumor pathology upgrade in training cohort (B) ROC curve of the nomogram for predicting apical tumor pathology upgrade in internal validation cohort (C) ROC curve of the nomogram for predicting apical tumor pathology upgrade in internal-external validation cohort.

F| 9 of 12 FENG
I G U R E 5 (A) Calibration curve of the nomogram for predicting apical tumor pathology upgrade in training cohort (B) Calibration curve of the nomogram for predicting apical tumor pathology upgrade in internal validation cohort (C) Calibration curve of the nomogram for predicting apical tumor pathology upgrade in internal-external validation cohort.et al. of pathology upgrade, as indicated by our nomogram, are recommended to undergo more aggressive management strategies.

F
I G U R E 6 (A) Decision curve analysis (DCA) of the nomogram for predicting apical tumor pathology upgrade in training cohort (B) DCA of the nomogram for predicting apical tumor pathology upgrade in internal validation cohort (C) DCA of the nomogram for predicting apical tumor pathology upgrade in internal-external validation cohort.
Baseline characteristics of included patients.
T A B L E 1Abbreviations: F/t PSA, free to total PSA; IQR, interquartile range; PI-RADS, prostate imaging-reporting and data system; PSA, prostate-specific antigen; PSAD, PSA density; PV, prostate volume; RP, radical prostatectomy.

tumor upgrade 95% CI for odds ratio Characteristics p-Value Odds ratio Lower Upper
Baseline characteristics of training group and validation group.Multivariable analysis for apical tumor pathology upgrade.
T A B L E 2Abbreviations: F/t PSA, free to total PSA; IQR, interquartile range; PSA, prostate-specific antigen; PSAD, PSA density; PV, prostate volume.F I G U R E 2 Kaplan-Meier curve showed the apical tumor pathology upgrade group had a significantly higher BCR rate than the non-upgrade group.T A B L E 3